The present invention relates to 2-imino-1,3-thiazine derivatives, in detail, 2-imino-1,3-thiazine derivatives having a selective antagonistic activity or agonistic activity to a cannabinoid type 2 receptor and pharmaceutical use of themselves.
Cannabinoid was discovered as the main active substance contained in marijuana in 1960 and found to exhibit an activity to the central nervous system (illusion, euphoria, sensory confusion of time and space) and an activity to the peripheral cell system (immunosuppressive activity, anti-inflammatory activity, analgesic activity).
After that, anandamide and 2-arachidonoylglycerol produced from phospholipid containing arachidonic acid were discovered as endogenous agonists to a cannabinoid receptor. These endogenous agonists were known to exhibit an activity to the central nervous system and an activity to the peripheral cell system. It was disclosed in Hypertension (1997) 29, 1204-1210 that anandamide exhibits an activity to the cardiovascular system.
A cannabinoid type 1 receptor discovered in 1990 was found to distribute in the central nervous system such as the brain. Agonists to this receptor were found to suppress the release of neurotransmitters to cause central actions such as illusion or the like. A cannabinoid type 2 receptor discovered in 1993 was found to distribute in immune tissues such as the spleen or the like. Agonists to this receptor were found to suppress an activation of cells in immunocyte or phlogocyte to exhibit an immunosuppressive activity, an anti-inflammatory activity and an analgesic activity (Nature, 1993, 365, 61-65).
Therefore, selective antagonists or agonists to the cannabinoid type 2 receptor are expected as immunosuppressive agents, anti-inflammatory agents, analgesic agents witout causing side effects on the central nervous system such as illusion or the drug dependence, which are associated with the cannabinoid type 1 receptor (Nature, 1998, 349, 277-281).
Known as compounds having an antagonistic activity or agonistic activity to the cannabinoid type 2 receptor are isoindolynone derivatives (WO97/29079 and WO99/02499), pyrazole derivatives (WO98/41519) and the like.
On the other hand, Japanese Patent Publications (Kokai 1986-65894, Kokai 1987-29594) disclose that organophosphorus compounds having a 2-imino-1,3-thiazine skelton are useful as insecticides.
However, it is not known that 2-imino-1,3-thiazine derivatives have an antagonistic activity or agonistic activity to the cannabinoid type 2 receptor.
The present invention provides 2-imino-1,3-thiazine derivatives or the like as novel compounds having a selective antagonistic activity or agonistic activity to the cannabinoid type 2 receptor.
The present invention comprises,
1) a pharmaceutical composition which comprises a compound of the formula (I): 
xe2x80x83wherein R1 is optionally substituted alkylene, R2 is alkyl; a group of the formula: xe2x80x94C(xe2x95x90R5)xe2x80x94R6 wherein R5 is O or S, and R6 is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl; or a group of the formula: xe2x80x94SO2R7 wherein R7 is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
2) the pharmaceutical composition according to the above 1) wherein the group of the formula: 
xe2x80x83is a group of the formula: 
wherein R3 and R4 each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic gruop, alkoxyiminoalkyl or a group of the formula: xe2x80x94C(xe2x95x90O)xe2x80x94RH wherein RH is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic gruop,
or R3 and R4 taken together may form alkylenedioxy, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle,
3) the pharmaceutical composition according to the above 1) or 2) which has a binding activity to a cannabinoid type 2 receptor,
4) the pharmaceutical composition according to the above 3) which has an agonistic activity to a cannabinoid type 2 receptor,
5) the pharmaceutical composition according to the above 3) which is useful as an anti-inflammatory agent,
6) the pharmaceutical composition according to the above 3) which is useful as an immunosuppressive agent,
7) the pharmaceutical composition according to the above 3) which is useful as a nephritis treating agent,
8) a compound of the formula (II): 
wherein R1 is optionally substituted alkylene, R2 is a group of the formula: xe2x80x94C(xe2x95x90R5)xe2x80x94R6 wherein R5 is O or S, R6 is alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aralkyloxy, optionally substituted aralkylthio, optionally substituted aralkylamino, alkoxyalkyl, alkylthioalkyl or optionally substituted aminoalkyl, or a group of the formula: xe2x80x94SO2R7 wherein R7 is alkyl, optionally substituted amino, optionally substituted aryl or optionally substituted heteroaryl, R3 and R4 each is independently hydrogen, alkyl, alkoxy, alkylthio, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, cycloalkyl, halogen, hydroxy, nitro, haloalkyl, haloalkoxy, optionally substituted carbamoyl, carboxy, alkoxycarbonyl, alkylsulfinyl, alkylsulfonyl, alkoxyalkyl, alkylthioalkyl, optionally substituted aminoalkyl, alkoxyalkoxy, alkylthioalkoxy, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, alkoxyiminoalkyl, or a group of the formula: xe2x80x94C(xe2x95x90O)xe2x80x94RH wherein RH is hydrogen, alkyl, optionally substituted aryl or optionally substituted non-aromatic heterocyclic group, or
R3 and R4 taken together may form alkylenedioxy, m is an integer of 0 to 2, A is optionally substituted aromatic carbocycle or optionally substituted aromatic heterocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
9) the compound according to the above 8) wherein m is 0, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
10) the compound according to the above 8) or 9) wherein R1 is a C2-C9 straight or branched alkylene optionally substituted with alkylene, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
11) the compound according to any one of the above 8) to 10) wherein R1 is a C2-C9 straight alkylene substituted with alkylene, or a C2-C9 branched alkylene, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
12) the compound according to any one of the above 8) to 11) wherein R6 is alkoxy or alkylthio, and R7 is optionally substituted aryl, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
13) the compound according to any one of the above 8) to 12) wherein R3 and R4 each is independently hydrogen, alkyl, alkoxy or alkylthio, and A is optionally substituted aromatic carbocycle, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
14) the compound according to the above 8) wherein R1 is 2,2-dimethyltrimethylene, 2,2-diethyltrimethylene, 2,2-ethylenetrimethylene, 1-methyltrimethylene, 2-methyltrimethylene, trimethylene, 2,2-di-n-propyltrimethylene, 2,2-tetramethylenetrimethylene, 2,2-pentamethylenetrimethylene, 1,1-dimethylethylene or 1-methylethylene, R6 is methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, i-butylthio, sec-butylthio, benzyloxy, benzylthio, methoxymethyl, ethoxymethyl, methylthiomethyl, ethylthiomethyl or ethylamino, R7 is methyl, ethyl, 4-tolyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-thienyl or 2-naphthyl, R3 is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, methylthio, ethylthio, n-propylthio, i-propylthio, dimethylamino, acetylamino, N-acetylmethylamino, diethylamino, ethylmethylamino, propylmethylamino, phenyl, phenoxy, fluoro, chloro, bromo, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, N-methylcarbamoyl, methoxycarbonyl, methanesulfinyl, ethanesulfinyl, methanesulfonyl, ethanesulfonyl, acetyl, methoxymethyl, 1-methoxyethyl, 3-pyridyl, morpholino, pyrrolidino, piperidino, 2-oxopyrrolidino, 1-methoxyiminoethyl or morpholinocarbonyl, R1 is hydrogen, methyl, ethyl, fluoro, chloro, nitro, methoxy or ethoxy, or
R3 and R4 taken together may form xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, A is benzene, naphthalene, pyridine or quinoline, a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
15) a pharmaceutical composition which comprises the compound according to any one of the above 8) to 14), a prodrug of itself, a pharmaceutically acceptable salt thereof or a solvate thereof,
16) the pharmaceutical composition according to the above 15) which has a binding activity to a cannabinoid type 2 receptor,
17) the pharmaceutical composition according to the above 16) which has an agonistic activity to a cannabinoid type 2 receptor,
18) the pharmaceutical composition according to the above 16) which is useful as an anti-inflammatory agent,
19) the pharmaceutical composition according to the above 16) which is useful as an immunosuppressive agent,
20) the pharmaceutical composition according to the above 16) which is useful as a nephritis treating agent,
21) a method for treating inflammation which comprises administering the pharmaceutical composition according to the above 1),
22) a method of immunosuppression which comprises administering the pharmaceutical composition according to the above 1),
23) a method for treating nephritis which comprises administering the pharmaceutical composition according to the above 1),
24) use of the compound according to the above 1) for manufacturing an anti-inflammatory agent,
25) use of the compound according to the above 1) for manufacturing an immunosuppressive agent, and
26) use of the compound according to the above 1) for manufacturing a nephritis treating agent.